The clinical manifestations of cystic fibrosis (CF), a common lethal hereditary disorder, are dominated by abnormalities of the airway epithelial surface, including chronic mucus production, infection, and inflammation (Boat et al., 1989). The gene responsible for CF, termed the "cystic fibrosis transmembrane conductance regulator" (CFTR) gene, is localized on chromosome 7 at q32 (Rommens et al., 1989; Riordan et al., 1989). The predicted CFTR protein is a 1480 residue single chain glycosylated molecule with twelve transmembrane domains and three intra-cytoplasmic domains containing sequences that can be phosphorylated by protein kinases (Riordan et al., 1989; Gregory et al., 1990). In vitro studies suggest that the CFTR protein is a Cl.sup.- channel that modulates the secretion of Cl.sup.- across the apical membrane of epithelial cells in response to elevations of intracellular cAMP (Anderson et al., 1991; Kartner et al., 1991). Mutations of the CFTR gene render epithelial cells unable to modulate Cl.sup.- secretion through the CFTR gene pathway (Frizzell et al., 1986; Li et al., 1988; Hwang et al., 1989). Importantly, in vitro studies have shown that transfer of the normal CFTR cDNA to epithelial cell lines derived from individuals with CF can override this abnormality, and permit the cells to secrete Cl.sup.- in response to increased intracellullar cAMP (Drumm et al., 1990; Rich et al., 1990).
These in vitro studies, and the knowledge that the lethal consequences of mutations of the gene occur almost exclusively in the lung (Boat et al, 1989), suggest the feasibility of somatic gene therapy for CF, i.e., it may be possible to correct the pulmonary manifestations caused by mutations of the CFTR gene by directly transferring a normal CFTR cDNA to airway epithelial cells in vivo. The major obstacles to this approach lie in the geometry of the lung and the biology of the airway epithelium. jthe epithelial cells of the human airway comprise an approximately 1-2 m.sup.2 surface distributed over a successively branching "fractal-like" tree structure (Weibel, 1991), a geometry that makes it essentially impossible to treat CF successfully by removing the epithelial cells for in vitro correction and subsequent reimplantation. Further, the majority of the airway epithelial cells are terminally differentiated and those that are capable of proliferating do so at a slow rate (Evans and Shami, 1989).